Thiazinyl derivatives of o-phenylenediamines

ABSTRACT

THIAZOLINYL AND THIAZINYL DERIVATIVES OF O-PHENYLENEDIAMINES ARE PROVIDED HAVING THE STRUCTURE   1-(H2N-),2-(-NH-C&lt;(=N--S-)-R2),(R1)N-BENZENE   WHEREIN R1, R2 AND N ARE DEFINED HEREINAFTER AND WHICH ARE USEFUL AS DISINFECTANTS, AND AS STARTING MATERIALS IN THE PREPARATION OF BENZIMIDAZOLES WHICH ARE USEFUL AS ANTHELMINTIC AGENTS, AND ALSO DYES.

ni d States atent 3,833,569 THIAZINYL DERIVATIVES F O-PHENYLENEDIAMINES Venkatachala L. Narayanan, Hightstown, and Rudiger D. Haugwitz, Titusville, N.J., assignors to E. R. Squibb & Sons, Inc., Princeton, NJ.

N0 Drawing. Original application Feb. 28, 1972, Ser. No. 230,121. Divided and this application Mar. 5, 1973, Ser. No. 338,002

Int. Cl. C07d 93/06 vs. Cl. 260-243 R 4 Claims ABSTRACT OF THE DISCLOSURE Thiazolinyl and thiazinyl derivatives of o-phenylenediamines are provided having the structure wherein R R and n are as defined hereinafter and which are useful as disinfectants, and as starting materials in the preparation of benzirnidazoles which are useful as anthelmintic agents, and also dyes.

This application is a division of United States application Ser. No. 230,121, filed Feb. 28, 1972.

The present invention relates to thiazolnyl and thiazinyl derivatives of a-phenylenediamines having the structure IITH represents a 5- or 6-membered ring containing 3 or 4 carbon atoms, respectively, wherein the additional 2 or 3 carbon atoms (not shown) may include a substituent other than hydrogen as indicated above.

The lower alkyl groups represented by the above R groups include straight or branched chain aliphatic hydrocarbon radicals having up to seven carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl, and the like. The lower alkyl groups can include as substituents any of the aryl groups mentioned below as well as halogen.

The alkoxy group or that portion of the alkoxy-carbonyl group includes straight and branched chain radicals Patented Sept. 3, 1974 of up to and including seven carbon atoms, corresponding to the above alkyl groups, e.g., methoxy, ethoxy, propoxy, isopropoxy, and the like. The aryloxy groups or that portion of the aryloxycarbonyl group includes any of the aryl groups set out below.

The term halogen includes each of the four halogens, but fluorine and chlorine are preferred.

The amino groups include unsubstituted as well as monoor di-lower alkyl-, arylalkyl-, lower alkylarylor arly-amino wherein lower alkyl and aryl are defined herein, such as rnethylamino, ethylamino, heptylamino, dimethylamino, diethylamino, ethylmethylamino, butyl methylamino, ethyl i-propylarnino, benzylamino, and the like.

The term aryl includes monocyclic or bicyclic monovalent aromatic ring systems such as phenyl or naphthyl. These aryl radicals can include as substituents halogen, nitro, trifiuoromethyl, alkoxy, amido, or any of the alkyl groups mentioned hereinbefore.

The acyl and aroyl groups included herein are derived from hydrocarbon carboxylic acids of less than twelve carbon atoms, which may be exemplified by the lower alkanoic acids (e.g., formic, acetic, propionic, butyric, valeric, trimethyl acetic and caproic acids), the lower alkenoic acids (e.g., acrylic, methacrylic, crotonic, 3-butenoic and senecioic acids), the monocyclic aryl-carboxylic acids (e.g., benzoic and toluic acids), the monocyclic aryllower alkanoic acids [e.g., phenacetic, p-phenylpropionic, a-phenylbutyric, and 5-(p-methylphenyl)pentanoic acids], the cycloalkyl carboxylic acids (e.g., cyclobutane carboxylic acid, cyclopentane carboxylic acid and cyclohexane carboxylic acid), the cycloalkenyl carboxylic acids (e.g., 2-cyclobutene carboxylic acid and 3-cyclopentene carboxylic acid), the cycloalkyl and cycloalkenyl-lower alkanoic acids [e.g., cyclohexaneacetic, u-cyclopentanebutyric, 2 cyclopenteneacetic and 3 (3 cyclohexene)pentenoic acid], and the like.

Examples of compounds falling within the invention include, but are not limited to, the following set out in Table A below:

TABLE A.

R n R 2 CH3 (4, 5) 2 Same as above 3 C1 (4 5) 2 Do. 4 c1 (45 1 Do. 5.-

(EH30 (4) 1 Do. 6 O 1 Do. 7 N0 (4) 1 Do.

8 04H (4) 1 I=.N l C 3 9 Br (3) 1 Same as above.- 10 Br (3), CEO (5) 2 Do.

11 Br (5), CH3 (3, 4) 3 (N 12 C'iHQO (4, 5) 2 Same as above. 13 C1 (3, 5) 2 Do.

TABLE AContinued Compounds of formula I are prepared by treating an o-phenylenediamine of formula 11 with a haloalkyl isothiocyanate of formula In. The resulting hydrohalides I can be converted to the free base, if desired.

1 J NH, L, NH: (R1) 1: 11

III 1 HX H o) wherein X is C1 or Br.

The above reaction may be carried out at a temperature within the range of from about 15 to about 150 C. in the presence of a hydrocarbon solvent such as benzene, toluene, glyme, ethyl ether, and the like, employing a molar ratio of II:III within the range of from about 1:09 to about 1:1. The reaction proceeds in the absence of external base and surprisingly, mono-substituted products are obtained even though there are two potential reaction sites in the starting o-phenylenediamines II.

Alternatively, compounds of formula I can be prepared by reacting a monothiourea with an inorganic mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid to yield I. For example, this reaction can be illustrated as follows:

N NH:

NE NH He A 8 NH N R -CH H3 RLGHPL g 4 The starting o-phenylenediamines II can be prepared by methods reported in the literature as well as apparent to one skilled in the art.

Examples of starting compounds of formula H include:

TABLE B H HHPHNOJWHHHHMNNH HI-IH The monothioureas IV are prepared by reacting compound II with one mole of an allylisothiocyanate V;

V IV NE: A

at a temperature Within the range of from about 20 to about C., in the presence of a solvent such as methanol, ethanol, benzene, toluene, or an ether such as ethyl ether or glyme, employing a molar ratio of II:V within the range of from about 1:1 to about 1.5 :1, and preferably 1:1.

The haloalkyl isothiocyanates III are readily prepared from their corresponding haloalkylamines 1V and thiophosgene.

X NH: 0801: kJ

which SON-CHzCH-Cl The compounds of formula I form physiologically acceptable acid-addition salts with inorganic and organic acids. These acid-addition salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with a base such as sodium hydroxide. Then any other salt may again be formed from the free base and the appropriate inorganic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, oxalate, tartrate, maleate, fumarate, citrate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like.

The compounds of formula I may be used as surface disinfectants. About 0.01 to 1 percent by weight of any of these substances may be dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. They may be incorporated also, for example, in a soap or other cleansing agent, e.g., a solid or liquid detergent, detergent composition, for example, in general cleaning, in cleaning dairy barns or equipment or cleaning food handling or processing equipment.

The compounds of the invention I are also useful in the preparation of benzimidazole anthelmintics or antiinflammatory agents disclosed in application Ser. No. 230,122 entitled Thiazolinyl and Thiazinyl Derivatives of Z-Aminobenzimidazoles by Haugwitz and Narayanan filed Feb. 28, 1972.

The following examples further illustrate and represent preferred embodiments of the invention.

EXAMPLE 1 2- (o-Aminoanilino)-2-thiazoline A solution of 7.8 g. (0.07 mole) of o-phenylenediamine and 11.9 g. (0.07 mole) of 2-bromoethyl isothiocyanate in 150 ml. of dry glyme is stirred at room temperature for one hour. The solvent is then decanted and the viscous oil that remains is taken up in water, basified with potassium carbonate and extracted with warm chloroform. The combined chloroform extracts are washed with water and cooled in an ice-bath. The crystals that precipitate are collected by filtration and dried to yield 6.6 g.; recrystallization from chloroform, m.p. 165- 167 C.

Anal.-Calcd for C H N S: C, 55.92; H, 5.73; N, 21.74. Found: C, 55.73; H, 5.82; N, 21.87.

EXAMPLE 2 2- (2-Amino-4 (or 5 -nitroanilino) -5,6-dihydro- 4H-1,3-thiazine 15.3 g. (0.1 mole) of 4-nitro-o-phenylenediamine (Aldrich) is dissolved in 200 ml. of dry glyme. To this solution 18.0 g. (0.1 mole) of 3-bromopropyl isothiocyanate is added and the mixture stirred overnight at room temperature. The precipitated product is collected and recrystallized from methanol to yield 18.1 g., m.p. 196-198 C. yellow needles.

Anal.'Calcd. for C H N SBr: C, 36.06; H, 3.94; N, 16.81. Found: C, 36.36; H, 4.14; N, 16.93.

6 EXAMPLE 3 2- o-Amino anilino -5 -methy1-2-thiazoline To 10 g. of 1-allyl-3-(o-aminophenyl)-2-thiourea there is added 40 ml. of concentrated hydrochloric acid and the resulting solution is kept at room temperature overnight. The solution is basified with concentrated ammonia and the resulting precipitate is filtered off and washed with water. Recrystallization from methanol yields 7.5 g.; m.p. 182 C.

AnaL-Calcd. for C H N S: C, 57.84; H, 6.32; N, 20.27. Found: C, 58.02; H, 6.27; N, 20.16.

EXAMPLE 4 2- (2-Amino-4,S-dimethylanilino -2-thiazoline Following the procedure of Example 1 but replacing 0- phenylenediamine with 4,5-dimethyl-o-phenylenediamine, the title compound is obtained, m.p. 178180 C.

Anal.Calcd. for C H N S: C, 59.70; H, 6.83; N, 18.99. Found: C,.59.48; H, 6.92; N, 19.05.

EXAMPLE 5 2- (2-Amino-4,5-dimethylanilino -5,6-dihydro-4H- 1,3-thiazine, hydrobromide (1: 1)

2.7 g. (0.02 mole) of 4,5-dimethyl-o-phenylenediamine is dissolved in 200 ml. of dry glyme. To this solution 3.6 g. (0.02 mole) of 3-bromopropyl isothiocyanate in ml. of dry glyme is added in a dropwise manner over a period of about one hour. After the reaction has proceeded for about 0.5 hour, a white precipitate begins to form. The reaction mixture is allowed to stir at room temperature for three hours and the precipitated white crystals are filtered off and washed with ethanol and ether to yield 4.1 g., rn.p. 124127 C.

AnaL-Calcd. for C H N S-HBr: C, 45.57; H, 5.74; N, 13.29. Found: C, 45.46; H, 5.77; N, 13.27.

EXAMPLE 6 2-(2-Amino-3 (or 4)-nitroanilino)-2-thiazoline-HBr A solution of 7.7 g. (0.05 mole) of 4-nitro-0-phenylenediamine and 8.3 g. (0.05 mole) of 2-bromoethyl isothiocyanate in ml. of dry glyme is refluxed on a steam bath for one hour. The solid precipitate is filtered off and washed with water and ethyl ether to yield 8.3 g. The product is recrystallized from methanol to yield the analytically pure title compound, mp. 204206 C.

EXAMPLES 7 TO 40 Following the procedure of Examples 1 and 2 but substituting the o-phenylenediamine derivative shown in column 1 of Table I below and the aliphatic haloalkyl isothiocyanate shown in column 2, the product shown in column 3 is obtained.

Where the o-phenylenediamine starting material is monosubstituted and includes a substituent at the 4 or 5 position, then the product shown in column 3 will include the S-tautomer or 4-tautomer, respectively; where the 0- phenylenediamine starting material is monosubstituted and includes a substituent at the 3- or 6-position, then the product shown in column 3 will include the 6-tautomer or 3-tautomer, respectively.

EXAMPLES 41 TO 47 Following the procedure of Example 3 and utilizing the monothiourea derivative in column 1, Table -II, and the mineral acid shown in column 2, the product shown in column 3 is obtained.

TABLE IContinued Column 1 Column 2 Column 3 i j Example R (position) 1 Haloalkylisothiocyanate (B (position) i 36 01H; (6) 1 SCNCHZCHQBI .d0 Same as above.

37..-. N01 (6) 1 SCNOHzCHzCHzBl -d0 A 38 C1 (4) 1 Same as above do Same as above. 39 CaHn (4) 1 SCNCHZCHAI'JHBI do A CaHi S N CaHaU 40 H r--- SCNCHzCHN'JHCI :.....d0 Same as above.

CaHs

TABLE II Column 1 Column 2 Column 3 NHg NH: (RIM: (Ron f NE A S NHCH2CH=C R H R2 Ex. R (position) 'n, R Acid (B (position) R 41-.--.. CH3 (4,5) 2 H HCI As in COlumnl CH3 42.-.-.. Oz (4) 1 H H01 --.-.d0 CH; 43... C4Hg (4) 1 H HCl 44-.-" (I) (4) 1 H H01 45"... H CH3 H H H H01 47".-- 01 (4,5) 2 H HCl What is claimed is: ring system; and physiologically acceptable acid-addition 1. A compound having the structure: salts thereof.

2. A compound in accordance with Claim 1 having the name 2-(2-amino-4-nitroanilino)-5,6-dihydro-4H-1,3- on thiazine.

NH 3. A compound in accordance with Claim 1 having wherein each R can be the same or different and is se-- lected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl, nitro, lower alkanoyl, lower alkenoyl, moncarbocyclic aroyl, monocarbocyclic aryl-lower alkanoyl, cycloalkanoyl, cycloalkenoyl, cycloalkyl-lower alkanoyl, cycloalkenyl-lower alkanoyl, lower alkoxy, aryloxy, tritfluoromethyl, lower alkylthio, arylthio, halo, cyano, amino, monoor di-lower aikylamino, monoor diarylalkylamino, monoor di-lower alkylarylamino, and monoor diarylamino; R is selected from the group consisting of hydrogen, lower alkyl, aralkyl, aryl and lower alkylaryl; n is 1, 2, 3, or 4; wherein the term aryl, unless otherwise limited, refers to a monoor bicarbocyclic aromatic the name 2-(Z-amino-S-nitroanilino)-5,6-dihydro-4H-1,3- thiazine.

4. A compound in accordance with Claim 1 having the name 2 (2-amino-4,5-dimethylanilino)-5,6-dihydro- 4H-1,3-thiazine, hydrobromide.

References Cited UNITED STATES PATENTS 3,299,087 1/1967 Spivack et al 260-3063 3,749,717 7/1973 Haugwitz et al 260243 FOREIGN PATENTS 433,3 19 1967 Switzerland.

JOHN M. FORD, Primary Examiner US. Cl. X.R.

Patent No. Dated September 3, 1974 Inventor) Venkatachala L. Narayanan and Rudiger D. Haugwitz It is certified that error appears in thehbove-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 34, the word "thiazolnyl" should be:

- thiazolinyl line 10, the word "arly-amino" should be:

-- aryl-amino Column 2,

line 63, the word "haloalklisothiocyanates" should be:

- haloalkylisothiocyanates Column 4,

Example 22, Column 1, under R (position) should read:

-- C H S (3) Example 25, Column 1, under R (position), should read:

-- CH o (4) Example 36, Column 1, under R (position) should read:

-- C H O (6) Signed and sealed this 12th day of November 1974.

Column 7,

Column 7,

Column 9,

(SEAL) Attest:

MCCOY M. GIBSON JR. Attesting Officer c. MARSHALL DANN Commissioner of Patents FORM PC4050 (10-69) usComm-oc 60376-P69 0.5, GOVERNMENT PRINTING OFFICE: 19'' O-JGG-JSI. 

